Gateway platform for biological monitoring and delivery of therapeutic compounds

ABSTRACT

The invention relates to methods and devices for remote or distributed continuous monitoring of physiologically relevant states. The invention provides for methods to automatically detect deviations or other states in physiological parameters and automatically alert a measured subject, user or other authorized party. The device provides for a universal platform for sensors, and further provides for the automatic compensation or distribution of devices or bioactive agents at appropriate levels and/or intervals in response to deviations or other states sensed in various physiological parameters.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.10/032,765 filed Oct. 29, 2001, which claims the benefit of U.S.Provisional Application Ser. No. 60/301,897, filed Jun. 29, 2001. Theseapplications are incorporated by reference in their entireties.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to methods and devices for remote or distributedmonitoring of physiological states. The invention provides for methodsto detect deviations in physiological parameters through theestablishment of baseline values, either by direct inspection ofcompiled data or by computer aided analysis. The device provides for auniversal platform for sensors, which may also allow automaticcompensation or distribution of devices or bioactive agents atappropriate levels and/or intervals in response to deviations sensed invarious physiological parameters.

2. Description of the Related Art

Long-term monitoring of physiological parameters has been particularlyproblematic to implement. This type of monitoring may be essential inmany situations, especially for patients that exhibit transitoryphysiological abnormalities. The implementation of long-term monitoringcan help solve several problems for at-risk patient care such as: 1)allows continuous monitoring, alerting care givers and patients topotential problems while patients are away from a managed care setting;2) allows true baselines to be obtained, making deviations easier todetect; and 3) allows the automatic collection of important datanecessary to determine the efficacy or non-efficacy of therapeutictreatments.

Long-term monitoring is typically easier to accomplish fornon-ambulatory patients. There are many examples of devices that monitorphysiological parameters in a hospital setting such aselectrocardiograms, electroencephalograms, pulse, heart rate, bloodpressure, and so on. However, for individuals that lead an active life,very few options presently exist for long-term monitoring ofphysiological conditions. Most devices only measure periodically and areprone to measurement variations caused by technique, compliance or use.Most often, these devices require a professional to operate and monitorthe condition of the device, as well as to assure patient compliance inorder to maintain proper functioning of the monitoring instrument. Inaddition, biocompatibility issues with many of these external devicesare numerous, with side effects such as attendant skin irritations,increasing patient non-compliance with the monitoring devices.

Invasive devices can also introduce complications. Althoughnon-compliance and measurement variation issues may be decreased withsemi-permanent implantable sensors, biocompatibility issues are evenhigher. Implantable devices often have a shortened half-life, due torejection of the device in the patient, accumulation of biologicalmaterials on the device themselves or other events, including infectionand mechanical breakdown of the device. U.S. Pat. No. 6,092,530 providesa sensor on the implantable device, which monitors accumulation ofbiological material on the sensor itself, decreasing the need toinvestigate the state of the device through invasive measures. Thesensor is remotely interrogated by an external device viaelectromagnetic or high-frequency radio waves, triggering the sensor totransmit encoded data to the external reader device.

Other medical sensors have been described which measure variousphysiological parameters for remote monitoring. For example, U.S. Pat.No. 5,987,352 to Klein, et al. discloses a minimally invasive implantcoupled with a telemetry system that stores triggered electrocardiogramdata. This device records physiological events that meet a set thresholdparameter, which is subsequently downloaded to an external reader devicethrough external interrogation. U.S. Pat. No. 5,833,603 to Kovacs et al.provides a device for monitoring various physiological parameters andstoring identified data. Similarly, U.S. Pat. No. 4,854,328 to Pollackdiscloses an animal monitoring system, which comprises an implantabletemperature sensor, and transmitter, which transmits a signal, uponsensing a pre-determined threshold value, to a remote receiver. Becausethe devices record only data that satisfies a set threshold parameter,it is unsuitable for establishing baseline patterns necessary indetecting low frequency events. Both devices also require an externalinterrogator device, which prompts the transponder to download collecteddata to an external recording device.

Other wireless technologies enable measurement of various physiologicalparameters on externally-based or implanted biosensors. U.S. Pat. No.5,511,553 to Segalowitz also discloses a device which measures multipleelectrophysiological parameters that provide continuous monitoring in awireless fashion for assessment of cardiovascular condition inambulatory patients. U.S. Pat. No. 6,175,752 to Say et al. discloses ananalyte monitor which measures multiple physiological parameters andprovides for continuous monitoring in a wireless fashion. The devicealso provides for a drug-delivery system to alter the level of theanalyte based on the data obtained using the sensor. Although bothdevices combine the use of biological sensors with wireless transmissionof data, it does not appear that they provide for a long-lasting,biologically compatible system that allows continuous feedback andanalysis with a network-based system capable of relaying informationfrom remote sensors on a mammalian subject to a central data analysissystem. There exists a continuing need for long-term physiologicalmonitoring devices that provide sensors which reduce biocompatibilityissues and provides a wireless data-relay system which reliablytransmits bioparameter data, allowing continuous or periodic monitoringof a patient's or users physiological state.

SUMMARY OF THE INVENTION

Accordingly, one aspect of the present invention is to address theshortcomings mentioned above by providing for methods and devices whichallow the continuous or periodic monitoring of physiological conditions.Physiological parameters are monitored via sensors mounted within aBioInterface Head (BIH), which is linked to a Communication and ControlModule (CCM). The CCM controls the BIH function and automaticallytransmits converted and encrypted information to a Data Collection Unit(DCU) via remote telemetry. The information from the DCU is analyzed andmay be forwarded to a remote data management system which will allowaccess by the measured subject, caregiver or other authorizedindividuals by remote telemetry or other forms of communication (FIG.1). An automatic compensation delivery mechanism may also beincorporated into the device, which may deliver therapeutic agents,compounds or other materials in response to detected abnormalities orfluctuations in various physiological parameters, or to outsideauthorized command.

One aspect of this invention is a device which automatically andcontinuously or periodically monitors physiological conditions in vivousing surface or sub-surface implanted sensors linked to CCM's andDCU's. By continuously monitoring physiological parameters remotely orin a distributed environment, baseline or reference data can beobtained, allowing detection of deviations in measured subjects. Thedevice particularly distinguishes itself from long-term monitoringdevices currently available by: 1) improving measured data quality bydiminishing data variation caused by the user, technique or complianceissues; 2) converting, encrypting and identifying data for furthertransmission and processing of data; 3) incorporating a wirelesstransmission signal system (e.g. radio frequency, acoustic or optical)or other remote communication method to allow automatic transmission ofdata collected from the CCM/BIH assembly to either adjacent or remoteCCM's or DCU's; 4) reducing biocompatibility issues associated withimplantable sensors with the use of novel biomaterials and devices todecrease the adhesion or encapsulation of the biofluid access port bybiological processes; and 5) coupling the wireless signal system toenable a two-way wireless-based control system to allow controlled orautomatic delivery of compounds or devices from the CCM/BIH assembly.

In one aspect, the BIH assembly may comprise various types of sensingmechanisms, including thermal sensors (thermoresistors, thermocouples),electrical sensors (EKG, ECG, impedance, frequency or capacitance),optical sensors (photonic wavelength, colorimetric, turbidity), chemicalsensors (pH, biomolecules, gases such as CO₂, and other chemicalsensors), enzyme-linked sensors (glucose oxidase, phosphatase, coupledsubstrates (e.g. horseradish peroxidase or alkaline phosphatase andother enzyme-linked sensors)), radiation sensors (gamma, beta and otherradiation detectors), magnetic sensors (micro NMR circuitry and magneticspin state) and physical sensors, such as flow meters and pressuresensors. Alternatively, the sensor may also comprise a MEMS (MicroElectrical Mechanical Systems) or a MOEMS (Micro Optical ElectricalMechanical Systems) sensing device, comprising at least one cantileverbeam coated with polymeric compounds for detection of variousphysiological substances or conditions. The microcantilever beams allowincreases in sensitivity and specificity, as compared to currentlyavailable technologies, and simplifies detection by coupling the beam totransducers which measure changes in capacitance, resonant frequency, orother techniques used in detecting mass changes in the spring element ofthe cantilever beam. In still other embodiments, nanotechnology devicesmay be incorporated into the sensor head or other components of thedevice for more accurate detection, cellular manipulation andmeasurement of physiological parameters. In one embodiment the BIHassembly, as well as other components of the system, may containcomponents micron, submicron or nanoscale in dimension, furtherlessening the obtrusiveness of the device to wearer.

In another aspect, the BIH assembly of the sensor element comprisesmaterials that permit interaction of the sensor with the hostenvironment. This includes microchannels, gel, fine mesh, screen,membrane, filters or a microporous frit, which permit interaction ofsensors to the host environment while maintaining a segregated andsterile environment within the sensing element itself. This tends toextend the life of the sensor by preventing fouling of the biologicalsensor with macromolecules and other substances that can adhere onto thesensor mechanism.

In accordance with another aspect of the invention, the use ofspecialized biomedia can be incorporated into the sensing head deviceand may decrease the exposure of the sensor element to the externalenvironment. This biomedia system may also decrease the adherence of thesensor element onto the host tissue or layer, a large component of therejection mechanism of biological sensors. Moreover, the use of abiomedia system may lower trauma to the surrounding tissue or layer byproviding medium that is physiologically compatible with the host,mimicking the tissue environment in which the sensor is implanted. Inyet another aspect of the invention, growth factors, cell signaling andcell adhesion molecules will be integrated into the biomedia system,mimicking the tissue and further improving biocompatibility issues ofthe sensor implantation into the host species.

In other aspects, the biomedia may have gel-like properties at ambientroom temperature, whereupon exposure to higher body temperatures changesthe material to a fluid-like state and becomes less viscous. One utilityof this gel-like material may be its use as part of a calibrationprocess for the sensor elements. When the sensor is implanted on or intothe host, the sensor itself is shielded from the host environment by thegel-like material. As the temperature around the sensor increases, thegel-like material changes viscosity, freeing calibration molecules fromthe matrix that then enter into the sensor. The sensor can then beaccurately calibrated before being equilibrated into the hostenvironment. The bio-media may also be used as a process or methodduring manufacturing. The bio-media may also provide increased productshelf-life storage by insulating the sensors on the BIH from degradationcaused by ambient conditions such as temperature, humidity or otherdegenerative storage issues.

In another aspect of the invention, the BIH assembly, located on top orwithin the dermal layer, interacts with the CCM (Control andCommunication Module) that is also located on top or within the dermallayer. The CCM interacts with the sensor unit either directly through aphysical means (e.g. conductive wire, optical, acoustic or other means)or indirectly using a remote wireless-based signal and control system.The CCM also contains a power supply consisting of either a removable orresponder power source. The CCM and the BIH assembly, if located on topof the dermal layer, are attached to the host patient through abioadherence system, which allows minimal irritation of the outer bodysurface, thereby tending to decrease rejection and increase thelongevity of the BIH and CCM assemblies.

In one particular aspect of the invention, the BIH is monitoredexternally by direct communication with the CCM. The CCM canautomatically, and continually or periodically, download storedconverted and encrypted information to a Data Collection Unit (DCU). TheCCM may also automatically, and continually or periodically, downloadstored information to a remote or adjacent CCM in areas where signaltransmission may be problematic. Where communication between the CCM andDCU is possible, but not between the DCU and the remote databasemanagement system, the DCU may download information to another remote ordistributed DCU until communication linkage with the remote databasemanagement system can be established. The CCM is also capable ofreceiving processed information from a remote database managementsystem, DCU or adjacent or remote CCM, alerting the patient or userthrough a separate communication channel or method, such as through alocalized display (e.g. visual, physical or acoustic means (liquidcrystal display, organic light emitting diode (OLED) display,magnetically sensitive liquid ink displays, audio alarm, physicalvibrations or paging mechanism)), or telecommunications pathway.

According to another aspect of the invention, the Bio Interface Head(BIH) comprises a release system delivering therapeutic agents, whichare administered in response to detected changes in variousphysiological parameters. The release system contained within the BIHinteracts with the CCM and releases therapeutic agents in response toinstructions received from the CCM. The CCM can be programmed todirectly trigger delivery of therapeutic agents, or can be coupled to anexternal control circuitry, allowing remote monitoring of a patient'scondition and subsequent adjustment of therapeutic agents in order tostabilize various physiological indicators.

While the advantages and features of the invention have been describedabove, a detailed description of the invention can be found below withaccompanying embodiments. These embodiments are illustrative of the manyways in which this invention can be exploited, and further advantagesand features will become apparent through the detailed description ofthe invention and their accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other objects, advantages and features of the presentinvention will be more readily understood from the following detaileddescription of the preferred embodiments thereof, when considered inconjunction with the following drawings.

FIG. 1. Components of the Human Gateway System.

FIG. 2. Block level diagram of an embodiment of the system, whereinsensor information from the BIH is preliminarily processed by the CCMand transmitted to the DCU and remote database management system. Theremote database management system, based on information received by thesensor, is capable of providing feedback analysis to the DCU or CCM orboth.

FIG. 3. Illustration wherein a direct communication linkage isestablished between the CCM and BIH.

FIG. 4. Illustration wherein the BIH and CCM are integrated into onecomponent.

FIG. 5. Illustration wherein a direct communication linkage isestablished between the CCM and an implanted BIH.

FIG. 6. Illustration wherein an indirect communication linkage betweenthe CCM and a surface-mounted BIH (FIG. 6A) or an implanted BIH (FIG.6B) is established.

FIG. 7. Block diagram illustrating the use of more than one CCM to relaydata from the BIH.

FIG. 8. Block diagram illustrating the use of more than one DCU to relaydata from the BIH.

FIG. 9. Partial cross-sectional view of surface-mounted BIH and CCMassembly.

FIG. 10. Partial cross-sectional view of Invasive BIH and CCM assembly(FIG. 10A) and sensor head assembly (FIG. 10B).

FIG. 11. General requirements for electronics in BIH.

FIG. 12. General requirements for electronics in CCM.

FIG. 13. General requirements for electronics in DCU.

FIG. 14. Views of a surface mounted BIH/CCM assembly

DEFINITIONS

HUMAN GATEWAY (HG) Platform—This describes a system of components,devices, data management systems and services necessary to remotelymeasure bioparameters, collect the data in a wireless remoteenvironment, analyze and summarize the data and provide access to thisdata by the mammalian subject, clinician or authorized third party. Inaddition it may include a two-way secure communication system enabling amammalian subject and clinician to remotely communicate diagnosticknowledge and/or actions.

BIH—BioInterface Head. May include sensors, interface or sensor mountingfeatures, data communication features, and structures for limitingmovement or ensuring placement on the measured subject of the sensors.

CCM—Control and Communication Module. Contains circuitry and meansnecessary to receive signals from the BIH, other CCM's and DCU, processthose signals and/or transmit them to a DCU, BIH or another CCM.

DCU—Data Collection Unit. Contains circuitry and means necessary toreceive and send signals from at least one CCM, DCU or externaltransmissions from other telemetry systems e.g. cellular, pager, fixedtelemetry or other telemetry systems.

Biomedia—Specialized medium to decrease exposure of the sensor elementto the external environment. Biomedia may consist of material that isbiologically and physiologically compatible with the host patient,whereby the properties are such that external calibration standards ormarkers are incorporated into the device and are released upon insertionof the device into the host patient. Biomedia may consist of anyphysiologically compatible reagent including, but not limited to:hydrogels, agarose, gelatin, starches, or any other natural orartificial polymeric compound.

Body surface—Body surfaces covered by epidermis or other related celltypes and exposed to the external environment, either continually ortransiently without piercing or otherwise penetrating the integrity ofthis surface. Examples of these surfaces include but are not limited to:skin or internal surfaces such as the mucosal surfaces that are found inthe mouth, nasal passages, or other body passages.

Conditioned Data—data received from the BIH and processed to removeextraneous noise or signals, as well as other procedures for enhancingsignal quality and transmission.

Continuously—Application-dependent frequency of measurement notrequiring user intervention.

Database Management System—Computer-based management system forprocessing, storing and summarization of sensor data to determinephysiological parameters of the mammalian subject, detect deviations orabnormalities in the physiological parameters, determine the mode ofaction in response to an analysis of the physiological parameters or anyother analysis and processing of the data necessary in evaluation of themammalian subject. Control instructions in response to the processeddata may be transmitted back to the mammalian subject or otherauthorized personnel through a computer-based or wireless communicationsmeans.

Data Transmission Device—personal digital assistant, pagers or otherdevices capable of data transmission or receiving information orinstructions.

Encrypted Data—asymmetric or symmetric encryption of data received fromsensors into encrypted text. Allows the transmission of data andsubsequent receipt of the same to be performed on any available controland communication module or data collection unit.

Mammalian Subject—the human, animal or other organism in whichmeasurements are being collected.

Periodically—User or system-controlled measured frequency.

Processed Data—error diagnosis and/or correction and analog to digitalconversion or digital to analog conversion, as well as other means forenabling or enhancing the transmission of data.

Remotely located—not in physical connection to mammalian subject.

Subdermally—located beneath the dermal layer surface.

Subcutaneously—located beneath the skin surface.

Sensor—Mechanical, electrical or optical sensing devices that measureinformation such as physiologically relevant information (e.g.temperature, pressure, EKG, ECG, pH, biochemicals, biomolecules, gasessuch as CO₂, and other chemical parameters, enzyme-based parameters,radiation, magnetic and physical parameters, such as blood flow, bloodpressure or other physical parameters), or other information (e.g. bodypositioning, GPS location).

Wireless means—radio frequency, acoustic or optical means fortransmitting and receiving information.

DETAILED DESCRIPTION OF THE INVENTION

The devices and methodologies of this invention provide a platform forthe mounting of biosensor modules useful for the monitoring ofbio-parameters including, but not limited to: physical measurements;e.g. temperature, motion, electrical, conductivity and pressure;(Wheatstone bridge measurements), chemical measurements, e.g.concentration of salts, drugs, metabolites, hormones, and pH; andbioactive assays, e.g. testing for the presence or absence ofantibodies, or other biomolecules or bioactivities from within themammalian subject. Once obtained, these data are transmitted from theBIH components to the CCM for compilation and response. Overall thedevice can be designated as a HUMAN GATEWAY (HG) platform (FIG. 1). Itis a unique feature of this invention that the data collection isautomatic, autonomous and unobtrusive. In addition, it may be linked toa two-way communication system, remote storage or data analysis system.

It is another unique feature of this invention that it may serve as aplatform onto which one or more sensors can be incorporated as neededand as sensor systems change. That is, it is a feature of the inventionthat the HG (HUMAN GATEWAY) platform provides the basic infrastructurefor a universal bioparameter monitoring platform. Another feature of theinvention is that the device may also serve to provide metered releaseof devices or delivery of suitable agents (e.g. therapeutics) to thebody through suitable components incorporated within the BIH. Thisinvention features a linkage between the BIH, containing at least onesensor module, CCM, and a remote DCU by use of a data relay systemutilizing a wireless-based data transmission system (e.g. RF, acousticor optical). This wireless-based system may be used to relay biometricdata and control signals from the BIH to the CCM as well as to and fromthe data collection unit (DCU).

In a preferred embodiment of the invention (FIG. 1), the HG is comprisedof three principle components. The first component 10 comprises theBioInterface Head (BIH) and Control and Communication Module (CCM). Thesecond component 30 is the Data Collection Unit (DCU), and the thirdcomponent 50 is the Database Management System. The CCM and DCUcomponents function to relay both bio-parameter measurements and signalsto and from sensor modules mounted or otherwise attached to the BIH,which may be attached to the CCM.

In operation (FIG. 2), the BIH 11 obtains bioparameter data from sensor12 measuring appropriate bodily conditions, states or composition, e.g.temperature, pH, or levels of defined biomolecules. The BIH 11 thencommunicates this data to the CCM 15. The CCM contains optimizedcircuitry necessary for basic data processing 14, signal processing 22,and data transmission 17. The CCM 15 relays the data stream to anadjacent DCU 30 unit. The DCU 30 units may be fixed at defined locations(e.g. fixed intervals in building corridors) or portable (e.g. worn orheld by the person being monitored). The CCM 15 may convert thebiosensor data stream from an analog signal to a digital signal 21(depending upon the sensor utilized), perform preliminary signalprocessing 22, display a limited form of data (i.e. current measuredvalue) and encrypt and encode identification tags 16 to the convertedand processed data. The DCU 30 can receive preliminarily processed data36, perform necessary additional signal processing 34, compilation ofsubsequently transmitted data sets 32 from the CCM 15 and store data 38as necessary. The DCU 30 may periodically transmit 36 the data to aremote database management system 50 for further signal processing 52(decryption, identification), analysis 52, summarization 58, storage 56and/or action 59. The database management system 50 may also, inresponse to the summarization of data received, feedback either to theDCU 62, CCM 64 or both.

In a preferred embodiment (FIG. 3), communication of the BIH 11 and CCM15 is through a direct physical link 76 to the BIH 11. Examples of themeans by which the CCM can be connected to the BIH 11 are: conductivewire, optical fiber, tape or nylon filaments, silicon microvia channelsor other methods that physically link the BIH to the CCM.

Alternatively (FIG. 4), the BIH 11 is linked 78 to the CCM 15 fabricatedassembly such that no clear delineation is visible between the twocomponents. In this embodiment, both components may reside on thesurface of the body.

In a second variation of this embodiment (FIG. 5), the CCM 15 isphysically linked 82 to the BIH 11, however, in this variation, the BIH11 is located below (or within) the body surface 84 whereas the CCM 15resides on the outside surface of the body. The location of theimplanted BIH may be sub-dermal, or located within deeper tissues orlayers or within organs of the body.

In yet another variation of this embodiment (FIG. 6), the CCM 15 is notphysically linked to the BIH 11. The CCM 15 resides on the outsidesurface of the body 84. The BIH 11 is located either on the outsidesurface of the body (but not physically linked; FIG. 6A), or isimplanted below the surface (but not physically linked; FIG. 6B). TheCCM 15 and BIH 11 communicate through a wireless means 86, such aselectrical, optical or acoustic transmission. The location and manner ofthe mounting of the CCM and BIH on the host body are determined by theapplication or bioparameters to be measured.

More than one CCM/BIH assemblies may be employed for measurement ofphysiological bio-parameters. Bio-parameters of the mammalian subjectare obtained by a plurality of BIH assemblies and collected withintra-device communication, signal monitoring and analysis, e.g.signal/time differential sensing of electrical impedance betweenmultiple assemblies. Variations of this approach would be the inclusionof multiple multifunctional CCM/BIH assemblies for data collection andtransmittal.

One feature of the present invention is that multiple CCMs may beemployed to provide a more robust communication of data to databases ifa DCU or mammalian subject is out of coverage range or experiences sometype of data transmission interruption or interference (FIG. 7). Forexample, a CCM #1 92 located on a subject transmits 94 the collecteddata from BIH # 1 93 and processed bioparameters to a CCM #2 96 locatedon an adjacent mammalian subject. CCM #2 96 would then transmit 98 datareceived from CCM #1 92 and its own collected bioparameter data from BIH#2 97 to an available DCU 100, which would then upload 104 both datasets to a remote database management system 102. The transmitted datafrom both CCM #1 92 and CCM #2 96 will be encrypted and encoded toensure that the information is secured and transmitted to authorizedcommunication devices only. This example may be extended to include twoor more CCMs to relay the data to a DCU.

Improved communication between devices may also be accomplished by analternative embodiment (FIG. 8), where multiple DCU's 118 and 128 areused to relay the bioparameter data to a remote database managementsystem 134 if the mammalian subject is out of coverage range orexperiences some type of data transmission interruption or interference.In this example, a CCM #1 112 receives bioparameter data from BIH #1114. CCM #1 112 transmits 116 the bioparameter data to DCU #1 118, whichin turn transmits 122 the signal to DCU #2 128. DCU #2 128, which alsoreceives 126 data from BIH #2 124 through CCM #2 122, transmitsbioparameter data from both BIH #1 114 and BIH #2 124 to a databasemanagement system 134.

Improved communication may also be achieved with the use of multipleCCMs receiving appropriately coded signals or data from a transmissionsource other than a DCU. Such a signal may take the form of a radiotransmission sent by common carrier transmitters, e.g. commercial radiostations, which may provide an alternative means to communicate to CCMassemblies. Such a communication means may prove useful for reaching oneor more measured subjects such as the need during natural disasters orcivil emergencies to ensure proper functioning of BIH/CCM assemblies.

BioInterface Head (BIH)

The Bio Interface Head assembly picks up one or more external orinternal measured parameters, which may include physiologicalparameters, biomolecules or foreign agents, and transforms them into aneasily processable signal, usually electrical or optical. The BIH iscomprised of several components. These may include, but are not limitedto, sensors, interface or sensor mounting features, data communicationfeatures, and structures for limiting movement or ensuring placement onthe measured subject of the sensors. A preferred embodiment of theinvention includes within the BIH at least one sensor which measuresphysiological parameters, e.g. temperature or pressure. Surfacetemperature sensors which can be placed on the thorax, armpit,extremities or other parts of the body surface (Exacon, Inc., D-SFL-1multipurpose temperature sensor, Wuntronic glass probe NTC ThermistorsSeries SP or other commercially available thermistor) can be mountedonto the BIH head for temperature measurements. Other sensors may alsobe included which measure EKG, ECG, pH, biochemicals, biomolecules,gases such as CO₂, and other chemical parameters, enzyme-basedparameters, radiation, magnetic and physical parameters, such as bloodflow, blood pressure or other physical parameters), or other information(e.g. body positioning, GPS location).

The measured data signal from the sensors may be conditioned at the BIHassembly to enhance the transmission to the CCM. Examples for suchconditioning are amplification, filtering or encoding. The signal isthen transmitted to the CCM. In cases where the BIH is integrated intothe CCM, the connection may be very short. The connection may consist ofan on-chip connection, which would minimize the distance between the CCMand BIH.

Depending upon the application, the BIH may comprise a contiguous unitwith the CCM whereas in other embodiments, the BIH may be a separateunit from the CCM, linked by either electrical, optical or other meansto convey data between the CCM and the BIH. The BIH may be a replaceableunit connected by physical or wireless means to the CCM. This featurepermits the ability to replace the BIH with either a new, different orreplacement BIH assembly while maintaining the same CCM. In addition,one design feature desirable in certain applications is that if the CCMor BIH is abruptly moved or otherwise displaced, it disconnects from theBIH such that the sensor system, including those forms transdermal inaspect, remain intact and non-moved.

The BIH, in addition, may also contain replaceable, disposable sensorsmounted within or otherwise attached to the BIH mounting unit. Thisfeature permits the ability to replace sensors within the BIH witheither new, different or replacement sensor units while maintaining thesame CCM-BIH assembly.

The BIH may utilize surface or non-invasive sensors for obtainingbioparameter data, such as temperature or pressure. Alternatively, theBIH may employ or mount sensors designed for obtaining subdermal (orfurther within the body) measurements. The form of the BIH willaccordingly differ depending upon the application, which governs thesensor selection.

The BIH may incorporate sensors that measure and/or transmit data eithermechanically, electrically, photonically or by other means. Addition ofcircuitry or other technology, e.g. photomultipliers, may be added basedupon signal-to-noise analysis with each type of sensor.

In addition, the use of photonic systems, e.g. vertical cavitysemiconductor laser (VCSL)—derived excitation, coupled to photodetectorpickup utilizing optics, e.g. fiber optics, or waveguides, for signaltransmittal from the sensor head may be used to communicate between theCCM and BIH. Again, dependent upon signal strength, it may be necessaryto locate some of the signal processing functions on the BIH. A photoniccoupled system may be less noisy than a corresponding electricalplatform, making photonic signaling between the BIH and CCM moredesirable in specific situations.

Compatibility of the BIH to the environment (e.g. biofluids) forextended periods will also factor into the design of the sensorplatform. Depending upon the environmental conditions, coatings (e.g.silicone, epoxy, synthetic polymers or other materials) or otherapproaches may be incorporated onto the sensor platform to extend BIHand/or CCM lifetime or to enhance biocompatibility.

A surface mounted BIH, as illustrated in FIG. 9, is a platform capableof measuring bioparameters from the measured subject with sensors. Insimple situations, the sensors 140 are in contact with the uppermostdermal or surface layer 142. An example of this can be found for surfacetemperature sensors placed on the thorax, armpit, extremities or otherparts of the body surface (Exacon, Inc., D-SFL-1 multipurposetemperature sensor, Wuntronic glass probe NTC Thermistors Series SP orother commercially available thermistor). In other situations,microsensors, such as microneedles utilized for conducting heat totemperature sensors, may be extended in a transitory fashion from thesurface mounted head in order to obtain readings.

The unit itself may be packaged along with the CCM 145 as shown, or maybe separated from the CCM but linked to the CCM via conductive wire,optical fiber or other data transmission methods. Sensor systems,mounted within the BIH, may deliver electrical, optical or other type ofdata signal to the CCM depending upon the sensor type utilized. The unitwill also include a transmission and receiving device 146, as well as apower source 148.

Mounting the BIH onto the surface may be done by adhesive patch 152 orby other methods which attach the assembly to the surface or any definedlocation on the body, e.g. on the skin, tooth surfaces, oral cavity orwithin other body cavities.

An invasive BIH (FIG. 10) is designed to serve as a platform forbiosensors monitoring bioparameters internally or below the surface ofthe body. It is also designed to link the data to and from these sensorsto the surface mounted CCM. One feature to the invasive BIH is itsfunction of linking subdermal (or deeper) sensors to the CCM whileminimizing infection and rejection by the host. As such, it may containseveral aspects to a design.

An invasive BIH may typically have three main tasks. The first task isto serve as a path or avenue to allow the sensors access to the internalenvironment, including internal biofluids (e.g. blood, lymphatic fluids,ductual fluids, or any other fluids produced by the body). Thisenvironment may be subdermal or located deeper within the body, e.g. theperitoneal cavity, intramuscular, or organs. The second is to anchor orlocate a signal transmission device and the third is to hold a sensor ormount for a replaceable, insertable sensor assembly.

These features or tasks are illustrated in FIG. 10. There may be otherdesigns and structures which perform these tasks that are also possible,and this embodiment is not intended to limit the scope of thisinvention. This design has four main components. The first of this isthe external mounting ring 162. This feature is to be made of an inert,hypoallergenic material, e.g. stainless steel, nylon or any othermaterial which does not cause an allergic reaction in the body. Mountingpoints may be contained on this ring for the external portion of thereplaceable, insertable sensor assembly. Anchoring this ring to thedermal layer 164 may be done by utilizing both adhesives 166 and thephysical compression of the tissue surrounding the transdermal portion,or any other method which will anchor the ring to the dermal layer. Theadhesives employed may be both conventional biocompatible syntheticadhesives as well as materials utilizing the bodies' own ability to formfibrous, contained structures contiguous to the dermal layer (theequivalent of a common scab). This latter point may be accomplished bycoating the lower aspect of the mounting ring with appropriate growthfactors, adherence molecules and attractants, such as prothrombinactivator, vitamin K, thrombin, fibrin, keratinocyte growth factor,activin, proteoglycans, cytokines, chemokines, TGF-beta, TNF-alpha,VEGF, PDGF, FGF, PAF, NGF, IL-4, IL-8, Insulin-like growth factor,integrins, laminin, fibronectin and other factors which promote thecutaneous wound-healing mechanism and formation of an epithelial-likestructure around the mounting ring.

Extending below the mounting ring is the second component (transdermalconduit 172), which is a structure (e.g. tube or filaments), that servesas the guide for the insertable sensor assembly. The transdermal conduitis a semi-permanent tube or structure that may be inserted by aclinician and is not intended to be routinely removed or replaced by themeasured subject or clinician. In most embodiments, this tube isflexible, hypo-immunogenic and possesses one or more hollow cores. Avariety of materials have been employed in the health care industry foruse as catheters, including silicon polymers, which have the appropriateductility and biocompatibility. If necessary, the outside wall may becoated with additional polymers to increase biocompatibility andminimize the possibility of rejection, e.g. polyethylene glycol or otherrelated polymeric materials. To provide additional mechanical strength,a laminate interior comprised of nylon or high strength fiber mesh maybe added, e.g. KEVLAR (a nylon laminate), which adds strength whilemaintaining the required flexibility. Flexibility and ductility areelements for comfort and acceptance of this implant technology.

At the end of the transdermal conduit is the third component, the sensormounting head 182. This mounting head may also facilitate insertion ofthe implantable BIH assembly. The mounting head will also be composed ofrigid biocompatible materials, such as nylon or other materials thatwould increase the rigidity of the structure. However, in order tominimize fibrous growth in the region of the implant, it may be coatedwith appropriate adhesion bio-molecules and/or growth factors to mimicthe surrounding environment and aid in the integration of the deviceinto the surrounding tissue. In addition, anticoagulation aids (e.g.heparin or other pharmaceutical anti-coagulants) may be present toprevent the adhesion of platelets or other clotting/rejection factorsonto the sensor head. The integration of the head into the surroundingtissue may be necessary in order to minimize physical disruption ofadjacent cells during routine motion on the part of the individual,thereby lessening encapsulation of the device by fibrous tissue as partof the body's rejection mechanism.

Contained within the head is the fourth structure or component, thebiofluid access port 184. This feature provides the means for biofluidsto pass into the device for analysis while simultaneously avoidingcontamination from the outside environment. To accomplish this, a finemesh, membrane or frit, or any other material which would provide abarrier for the sensor head, may be employed to prevent the transferenceor transmission of pathogens into the body. Certain micro-structures,e.g. MEMS or MOEMS based structures, formed with microvias,micro-sphincters, micro-valves, micro-openings, or compositenanostructures having a porous character, e.g. a mesh, contained withina surrounding silicon chip can provide the necessary exclusion ofparticles while allowing fluid and small molecule passage for testing.In addition, this component will have the necessary structural featuresfor packaging within the rigid head component. In certain applications,the access port itself is part of the sensing system, e.g. a pressuresensitive device or thermal sensing unit. The biocompatibility issue hasbeen a significant challenge in prior devices. In particular, cellulardebris in the vicinity of the access port might lead to the developmentof a rejection response or render the sensor ineffective. To minimizethis risk, flushing of the vicinity in the region of the access port maybe necessary to remove cellular debris periodically. Flushing can beperformed either manually by the user, or automatically through the useof channels or compartments which release saline or otherphysiologically compatible solution upon the sensing of occlusion,rejection or other factors which may diminish the intended performanceof the device.

One approach to minimize performance degradation of the device is by theaddition of biocompatible fluids 196, e.g. blood substitutes,physiological saline, or other physiologically compatible solutionswhich may contain bacterio-static agents into the interior of thetransdermal conduit. These fluids would either back flush occludingmaterial out of the transdermal conduit or, by virtue of the hydrostaticpressure generated by inserting the BIH assembly 194 into the conduit,force the small amount of cellular debris adjacent to the access portinto the surrounding extracellular fluid or interstitial space aidingthe body's own mechanism to flush the material away. Other approachesinclude the addition of appropriate adhesion factors (integrins,laminin, fibronectin and other adhesion factors) to augment theintegration of the access port to the surrounding cells, coupled withthe use of other microdevices, e.g. MEMS or MOEMS, that remain sealeduntil activated. Upon activation (based upon communication from theoutside system through the BIH assembly), vias open up within the microdevice, resulting in micropassages into which extracellular fluid mayflow. Micron scale “scrapers” within the microdevice may also beemployed in conjunction with flushing to remove debris and gain accessto interstitial fluid. Additional approaches, e.g. the use ofelectrical, or photonic forces, or chemical agents, may also be employedto sweep the charged biomolecules forming the cellular debris away fromthe access port and/or improve access port function. All of theseapproaches may be synergistically applied to provide access to biofluidsfor monitoring. A valved structure may also be utilized to control thequantities and sterility of the biocompatible fluids 196 used to flushthe transdermal conduit. This valved structure may be created byinsertion of the replaceable BIH assembly 194 into a valve means, whichwould aid in controlling the added biocompatible fluids 196 as w ell asregulate backpressure from infiltrating biofluids into the biosensorhead 182 and the transdermal conduit 172.

To aid with the manufacture, storage, in-field calibration and insertionof the BIH, a biocompatible hydrogel or similar substance may be used tocoat or encapsulate the BIH assembly 194. The conduit 172 and head 182may also be filled with this hydrogel. The hydrogel may containpreservatives, anti-inflammatory agents, anticoagulants, bioactiveagents, e.g. growth factors, cytokines or other bioactive agents, andantibiotics or antimicrobial agents. A form of hydrogel (e.g. selectagarose gels, carrageenan gels, collagen gels, or other biocompatiblesynthetic or natural gels) may also be employed which exhibits theproperty of either being gel or liquid in nature in atemperature-dependent fashion. In particular, at or around roomtemperature the material has high viscosity and is gel-like in nature.When raised to body temperature, the material becomes fluid and isabsorbed by the surrounding tissue.

Once the transdermal conduit 172 is inserted through the skin or outermembrane, a BIH platform 194 may be passed down through the center coreand positioned at the sensor mounting head. The action of inserting theBIH assembly 194 may be performed by a physician, other trainedpersonnel or the mammalian subject directly to replace or change the BIHas needed or as desired. In inserting the BIH assembly 194 down thetransdermal conduit 172, biocompatible fluid 196 containing antibioticsand other agents designed to facilitate biocompatibility,anti-inflammation, system sterility and enhance biomolecule access tothe sensor may be introduced. This may be accomplished by having a smallreservoir of fluid attached to the BIH assembly 194 and upon applicationof external force, e.g. manually squeezing the reservoir or any othermeans of depositing liquid, the fluid is forced down into thetransdermal conduit and flushes the conduit, head assembly and accessport. Alternatively, the BIH assembly being introduced may have a hollowcore through which the fluid may flow, and excess fluid will either passthrough the BIH into the surrounding tissue or back up the conduitwhere, by use of back flow valves, a sterile solution is preservedwithin the conduit and head assembly. In yet another embodiment, otherforms of gels, e.g. Pluronic F-127, which are liquid at room temperaturebut gel when elevated to body temperature, may be utilized to flush thetransdermal conduit 172 and then, upon gelling, provide a barrier tocontamination as well as some degree of structural support to thetransdermal conduit 172 and head/sensor assembly 182. In yet anotherembodiment, the BIH can be an integral part or mounted permanentlywithin or on the outside aspect of the conduit/head assembly.

In certain applications and embodiments, the mammalian subject's ownbio-environment, e.g. a rejection response to foreign objects ormaterials, may be employed to remove the implanted BIH. That is, the BIHmay be composed in part or entirety in materials having finite lifetimeswithin the body. At the end of the anticipated lifetime, a biocompatiblecoating would dissolve or degrade, exposing a non-biocompatible surfaceunderneath. Alternatively, components of the BIH may be comprised ofmaterials, e.g. collagens, that would be absorbed by the body over time.In other variations, agents to facilitate rejection, fibrous tissuegrowth or other means of isolating the BIH by natural mechanisms, may beadded through the transdermal conduit 172 to end the BIH's lifetimewithin the measured subject.

The BIH sensor head 182 will signal or otherwise indicate the type ofsensor employed as well as a unique identifier to the CCM 192. The CCM192, in turn, may communicate this information back to the DCU such thatthe data stream is analyzed for the correct physiological parameter andthe identity of the individual is linked to this analysis.

Independent Implanted BIH

An independent implanted BIH is similar in concept to the invasive BIHdescribed above with similar concerns about biocompatibility, biofluidsampling, etc. One feature difference is that the independent implantedversion does have a wireless means to the CCM. The entire device orpackage will be inserted, maintained and removed by qualified personnel,e.g. physicians, licensed nurses or technicians.

In order to communicate biosensor data, the independent implanted BIHassembly may include the necessary features from the CCM to enablecommunications with the DCU or will have a wireless communication linkto another CCM assembly (which may be surface mounted). In the formersituation, the design of the device will include both features of theimplantable transdermal conduit and head assembly, BIH and CCM as anassembly. In the latter case requiring data communication to another CCMassembly located elsewhere, a number of additional features such aspower source, data transmission, signal processing, and signalencryption capabilities may be built into the BIH assembly. Possiblepower sources for the BIH include batteries or responder (RF)technology. Alternatively, the measured subject's own energy, e.g.motion, internal chemistry, including ATP molecules, glucose, or otherenergy supplying compounds, or osmotic pressure, may supply the energynecessary to power the implanted BIH.

BIH Delivery System

The delivery of various compounds and materials, including, but notlimited to: therapeutic agents; molecular scale sensing devices ormaterials; bioactive substances; enzymes; proteins; gene therapy agents;viral-based bio-agents; and/or micro- or nano-scale devices ormaterials; may also be accomplished in certain embodiments using theBIH. These materials and/or devices may be delivered for a variety ofpurposes, including, but not limited to: the relief of detectedconditions; for preventative treatments; and as mobile sensors,detectors or other aids to diagnosis, treatment or measurement.

The reagents, materials, compounds or devices to be administered may bestored within reservoirs or other containment methods within the BIHand/or CCM assembly. The materials, compounds, devices, etc., may bestored in either biologically active or inactive states. The storageform may include aerosols; compressed gases; liquid storage, e.g.suspensions, solutions or gels; and/or dry forms of storage, e.g.powder, granules or films.

Upon receipt of appropriate data and instructions, the CCM will directthe release of some portion, e.g. all or a fraction, of the materialfrom storage in the BIH and/or CCM for delivery either to the surface ofthe measured subject or below the surface. In the latter case,transdermal delivery systems may include microprobes extending into orbelow the skin or other outer membrane, or utilize the transdermalconduit and access port of the invasive BIH assembly. In otherembodiments, the storage area and/or release site may include locationsor sites located on features built into the head or outside aspect ofthe BIH/CCM assembly. The delivery site and mechanism may also utilizemicrostructures, e.g. MEMS or MOEMS-based systems, integrated intoeither the BIH or CCM and may have micro-valves, microchannels, portsand switches.

The delivery mechanism may include, but is not limited to: fluidpumping; mechanical insertion; chemical reactions, e.g. production ofgases or pressure to aid delivery; or electrical means, e.g.ionophoretic transport. Alternatively, the delivery means may includethe removal or dissolving of protective layers from regions of the BIHupon instruction from the CCM, exposing the bioagents, materials ordevices underneath. The bioagents, materials, or devices to be deliveredmay be mixed with additional fluids or reagents, e.g. water,physiological compatible buffers and components, dimethyl sulfoxide orother solvents, to facilitate generation of active materials or theabsorption or uptake of the materials, compounds, etc. by the measuredsubject. Once added, the delivery system may signal the CCM as to theaddition of the compounds, materials or devices or the addition may bemonitored by sensors detecting either the agents directly or indirectlythrough bioparameters.

Control and Communication Module (CCM)

The CCM is the assembly which links the BIH and the DCU (Data CollectionUnit). Typically, the CCM receives data from one or more BIH assembliesand transmits the data to the DCU for further processing. The CCM isalso capable of receiving information or instructions from the DCU,another CCM or other communications device. Components comprising theCCM (Hardware or Software; FIG. 12) may include but are not limited to,the signal receiver from the BIH assembly, e.g. electrical, acousticalor photonic signals, a filter to remove extraneous signal and/or noise,memory buffer, analog to digital (A/D) conversion, error diagnosisand/or correction, signal encryption and identification coding, powersupply, power supply control, reception/transmission protocol, internaltime reference and a means to convey the digitized data to the DCU, suchas electrical e.g. radio transmission (RF), acoustic or opticaltransmission. Individual components comprising the CCM may varydepending upon the type of sensor used, the type and strength of thesignal from the sensors, the transmission environment and theavailability of DCU's or other receiving devices for transmitting andreceiving data or information.

In use, the CCM may take the form of a multifunctional chip assemblymounted onto an adhesive strip or other adhesive material for ease ofattachment onto the measured subject. Alternatively, the CCM might beplaced onto a device, a strap or integrated into clothing or apparel. Insome circumstances, it may be advantageous to mount the CCM internally,e.g. invasively or within a body cavity, in order to minimize deviceremoval and to facilitate use by increasing compliance.

The CCM may be at least one IC (integrated circuit) assembly which mayinclude the following functionalities on-board, depending upon theapplication and sensors used: A/D signal conversion, signal filtering,memory (Flash RAM/ROM, EEPROM, or other means to store data), controller(including, but not limited to CPU processing, custom microprocessor,one-time programmable microprocessor (OTP), multi-time programmablemicroprocessor (MTP), field programmable gate array (FPGA), programmablelogic controller (PLC) or other types of controllers that are availabledepending upon the available technology (nano-controllers, opticalrelays or electrical arrays) data binning, data transmission encryptionand a unique identification (ID tag) as well as functions that weredescribed previously for the CCM, (such as a power supply and antennaefor wireless signal transmission and reception to and from the DCU).These functions may be integrated onto a single chip, comprisingsilicon, gallium or germanium, depending upon the available technology.It may be incorporated into an adhesive patch or device to be worn bythe individual to minimize size or bulkiness and maximize comfort.

Modifications to the CCM assembly for adaptation to the implanted sensorplatform include but are not limited to the ability to incorporate abio-fluid reservoir and snap-off mounting to prevent dislodging thetransdermal conduit and BIH if the CCM or patch is violently jarred ordisplaced. Dependent upon the application, the BIH may also be directlyassembled onto the CCM assembly in order to reduce the cost and size ofthe product and improve signal reception from the BIH.

In operation, the CCM receives at least one signal from the BIH. The CCMmay amplify the signal through the use of an automated gain control orother means of amplification (e.g. operation amplifier). An analog todigital (A/D) conversion of the received signal from the BIH may beperformed if necessary. Other pre-processing methods, such as filteringor signal averaging, may be employed to improve the signal-to-noiseratio. The method employed depends on the type of sensor or applicationused. The pre-processing also may include error diagnostics (electricalsystem diagnostics, impedance and other error diagnostic protocols) todetect a problem in the CCM or BIH assemblies, or application, such ascommunication and/or sensor problem, e.g. a broken wire or an internalsensor fault. This function assures that no erroneous data is generateddue to a sensor fault or communication interruption/failure. An errorcorrection algorithm may also be incorporated to enhance the measuredsignal quality.

BIH and sensor identification (or ID management) is an attribute of theHG system. In particular, the ID management function ensures increasedaccuracy in sensor type employed and appropriate data tracking andhandling to the measured subject. This also enables the DCU toselectively receive information from CCM's that have been addressed tothis DCU. ID management provides information about a particular BIHassembly features such as the sensor type or serial number to the DCU.This information may enhance the data communication reliability andidentification of measured subjects in a densely distributed applicationsuch as a hospital or assisted living environment.

The pre-processed signal is transmitted from the CCM to the DCU. Thistransmission may be encrypted using unique encryption algorithms toprotect the data and allow security of transmission, especially wheremultiple CCM, DCU or both are used to relay the information.Furthermore, the transmission protocol may include elements, such asdiffering frequencies, modulation e.g. frequency hopping spread spectrum(FHSS), direct sequence spread spectrum (DSSS), timing, handshakes e.g.check sums. The transmission may be one-way or two-way, depending uponthe need for feedback of processed data or information to the mammaliansubject. The CCM may include hardware to enable transmission and receiptof signals from one or more BIH, CCM or DCU assemblies.

The CCM may include a time reference, such as an internal clock, forthose applications which require measured data to be correlated basedupon a time (relative or absolute) or expiration of time. This isimportant for many medical applications like ECG or heart ratemeasurement. In addition it may assist in the analysis of data basedupon the frequency of a particular measured event's occurrence or theabsolute time when a measured event occurred. It further assures correctcommunication timing necessary for monitoring of physiologicalparameters.

A power supply is essential for the operation of the BIH and CCMassemblies. It is preferably integrated into the CCM assembly. It maypower the BIH if power requirements exist, e.g. MEMS head assembly oractive sensors. Two possible solutions are a battery or a respondercircuit that is powered by an electromagnetic field e.g. inductively orcapacitively charged.

A power control function may ensure proper function while optimizing thepower consumption. It includes a start-up mechanism that controls thepower delivery to the circuits in order to initiate the firstmeasurement after a power-down phase, and may also include low power(sleep) settings to extend the device use. The system may includemultiple power sources to extend the device use e.g. battery andinductive recharging of battery. The power control function will managethe multi power source configurations.

A feedback device may provide simple user information. This may be forexample an light emitting diode (LED), piezo beeper or a mechanicalvibrator/clicker that may be used to indicate whether a measurement hasbeen completed successfully or whether an error has occurred. Inaddition, an alert/feedback mechanism may be employed in thosesituations where critical threshold parameters, e.g. temperature, areexceeded. This alert/feedback system would use the display (if present)and the feedback device (if present).

The CCM also may in certain circumstances contain a means of displayingthe data being transmitted, e.g. a flexible or rigid visible displaysuch as a liquid crystal display (LCD), organic light emitting diodedisplay (OLED), magnetically reactive polymer displays (e.g. electronicink), passive or active colorimetric or color based alert displays. Thedisplay unit may be mounted onto the CCM. Alternatively, the CCM maymount a simple audio alarm or alert.

Data Collection Unit (DCU)

The Data Collection Unit (FIG. 13) may interrogate the CCM and receive asignal from one or more CCM's. The DCU may convert the received signalinto a form that can be processed by the DCU control system e.g. amicrocontroller. The DCU is intended to have more extensive means fordata processing than the CCM. As a result, this may allow more complexsignal processing and analysis. This function may improve the analysisof signals received and may enable management of data received fromother applications. The results may be transmitted to a remote databasemanagement system through a communications network, e.g. a cellularphone network or the Internet. With this method, the data may beremotely collected, analyzed and summarized. The processed data may thenbe provided to other persons, e.g. a measured subject, clinician(physician), or authorized third parties. The receiving party may alsocommunicate back to the measured subject or other authorized third partyusing the same communication network. This may enable the measuredsubject and clinician to remotely communicate diagnostic knowledgeand/or actions resulting from review of processed data.

The utility of the device requires that the DCU have several attributes.These include, but are not limited to: the ability to transmit to and toreceive data streams from the CCM, to communicate these data tosecondary sites of analysis using such means as linkages throughinternet communication-based systems, cell phone-based communicationdevices, personal alpha-numeric paging networks or hardwired directcommunication systems configured to receive and analyze such datastreams. In addition, the DCU may also have a user input device, e.g. akeyboard, touch screen, as well as a display or actuators, e.g. abeeper, to serve as a user interface. A power supply for the DCU may bemobile, e.g. a rechargeable battery or it may be wirebound, such asmight be the case in wall mounted DCU units.

As such, one form of the DCU may be an accessory module placed within orotherwise connected to preexisting communication devices such as handheld cellular telephones and PDAs.

As the signal transmitted to the DCU may be weak, the DCU might bedirectly connected by wire or other means directly to the CCM.Alternatively, the DCU might be physically separate from the CCM andreceive the signal by such means, but not limited to, electrical,photonic or mechanical (e.g. acoustical) generated signals. The HGsystem as a whole collects more data and measurements over time, whichimproves the diagnostic knowledge on the mammalian subject.

The remote database management system will store, analyze and summarizedthe collected data in a real-time environment. Custom algorithms andneural analysis will be used to interpret the collected data, withmeasured subject or clinician controlled customizable variables. Thisanalysis will be summarized and either made available to the measuredsubject and/or clinician automatically by either posting the data in asystem which would display e.g. Web based portal, or transmit thesummarized data to the clinician and/or measured subject, thistransmission may be a through a wireless communication system, a landbased system e.g. phone call or facsimile, or printed and delivered tothe physical location e.g. U.S. Mail, or other mail delivery system.

The data may be transferred from the DCU into a data management systemwhich may further analyze the collected and transmitted signals/data.One of the advantages of the HG system with its continual monitoringallows the establishment of individual baseline measured bioparametersas well as inclusion in and comparison to a larger bioinformaticsdatabase. This may facilitate identification of individual deviations oranomalies, as well as discerning population trends. This contrasts withcurrent methods having transient or periodic measurements taken of anindividual, e.g. once a day/week, which are less likely to detectdeviations or anomalies.

Data Transceiving

For both the connections between BIH and CCM as well as between CCM andDCU, transmission protocols define how the data is transmitted (FIGS.11-13). They assure compatibility of different BIH, CCM and DCU modelsand high system reliability. The transmission protocols may vary incomplexity depending on the application. For example, a preferredembodiment in the case of a wire-bonded BIH-CCM link, would be atransmission protocol as an analog resistance signal that is read indefined intervals. If a wireless transmission is used, the transmissionprotocols will be much more complex. Another factor that has aninfluence on the transmission protocols is whether the transmission isunidirectional or bidirectional. Bidirectional transmissions allowcertain features like electronic handshaking, but require more hardwareand energy resources.

A protocol definition includes the physical characteristics of the dataconnection (e.g. RF or infrared radiation, frequency, modulation types).Further, the data transfer mechanism may be specified. This may includesynchronization and handshake mechanisms as well as repetition rates.The data structures of the protocol may define the amount of data thatcan be transferred. Typically the data is organized in blocks or packetsthat are sent repeatedly at specified intervals. As an example, aprotocol may define a transmission block consisting of synchronizationbits, an address field that contains ID information, a data fieldcontaining the data generated by the CCM from the BIH input and achecksum field allowing testing for data integrity at the receiver'send. The length of the data block variable may vary.-This will-be usefulin minimizing power consumption and maximizing device lifetime.

For two-way transmissions, an electronic handshake is possible where thereceiver indicates the successful reception of data. If the handshakesignal indicates that the data was not received correctly the senderunit may retransmit. If there is only one-way transmission of thesignal, it may be helpful to transmit the data signal more than one timein order to increase the likelihood of signal reception.

If a system is designed to have multiple devices sending data to one ormore receivers using one-way transmission, it may be advantageous to usedifferent repetition frequencies for the sending devices. Thus it maybecome more likely that sending devices do not interfere with eachother. This problem may not occur with two-way transmissions since thesending device transmits by request only.

Either custom or available protocols (e.g. GSM, Bluetooth or IP) may beused depending upon the application, devices, environmental conditions(e.g. high noise or signal interference) and transmission requirements.

Based upon the above considerations and those in previous sections, apreferred embodiment for wireless communication between the CCM and DCUwould be by RF using a frequency hopping spread-spectrum signalemploying wireless medical band frequencies, e.g. between 609 to 613 or1390 to 1395 MHz. The means to communicate would be two-way, employingelectronic handshaking between the sender and receiver. Thecommunication protocol would consist of information packets comprised offour sections: a header section; an 64 bit address section (thereforehaving 2⁶⁴ possible numeric combinations for the device identification);an encrypted data section (encrypted using an algorithm based upon theaddress section ID); and a check-sum or error correction section.

A preferred embodiment for wireless communication between a BIH assemblyand a CCM assembly would be similar to the above preferred embodimentdescribing communication between a CCM and DCU unit. Conversely, dataexchange between a DCU and higher level systems would employ existingcommunication protocols especially with regards to data encryption. Inthis case, a preferred means of encryption would be existing 128 bitTCP/IP based encryption at the SSL layer of signal transmission.

EXAMPLES

Uses and Applications of the HG include uses involving the measurementof physiological parameters, including but not limited to, temperature,blood pressure, heart rate, respiration, electrical measurements (e.g.EKG or ECG), pH, CO₂, pO₂, biochemical substrates (e.g. glucose oxidase,phosphatase, vitamins, nutraceuticals, hormone levels, etc.), radiationand magnetic spin states. The parameters may be useful indicators ofphysiological events, such as ovulation, or indicate abnormalphysiological events, such as microbial infection, heart attack ordiabetic shock.

Although the examples below are indicative of the type of uses the HGsystem can be applied to, they are not meant to limit the scope of theinvention. Those of ordinary skill in the art can appreciate the manyapplications that the HG system could be used in, and with no undueexperimentation, different sensors can be used to adapt to theapplication needed for each occasion.

Use of the HG to Monitor Temperature Changes in Patients

FIG. 14 depicts a HG configured to measure temperature changes either atthe surface of the epidermal layer or subsurface in the dermal layer.For temperature measurements at the surface, the CCM 204 and BIH 202 areintegrated into one single unit, where the BIH is in directcommunication with the CCM. A power source 208 and transmitter 210 areincluded, where all components are mounted on a suitable substrate 212,and attached to the mammalian subject using an adhesive patch 214. TheBIH contains sensors 206 that measure temperature changes, and canconsist of one of many types of temperature sensors. A preferredembodiment of surface temperature sensors are thermistors, which areminiaturized, semiconductor-based devices capable of high sensitivityand resistance to extreme environmental conditions. Thermistors arereadily commercially available (e.g. Precision Engineering, RTIElectronics, Inc., Wuntronic, Inc. and other manufacturers of NTC andPTC Thermistors), and can be custom fitted to many differentapplications. Temperature sensors can be placed on outer body surfaces,including the thorax, armpit, extremities and other body surfaces, aswell as within cavities, such as the nasopharynx airway, oral cavity andin the ear canal in close proximity to the tympanic membrane (Exacon,Inc., D-TM1 sensor). Other examples of suitable temperature sensorsinclude metallic wire (such as platinum) resistive temperature sensors,thermocouples, semi-conductor p/n junctions as well as othersilicon-based diode temperature sensors and band-gap based sensors.Temperature sensitive materials, such as liquid crystals, may also beutilized which have a detectable change in physical properties that isproportional to a change in temperature. Alternatively, temperaturesensors may consist of microneedles or other materials penetrating thedermis to more accurately measure the measured subject's temperature(Exacon, Inc. DN1205 and D-F1350A). The temperature in this case wouldbe measured by either thermistors or other gauges within the needles,etc. or by conducting the internal temperature back to the surface byheat conductive materials, e.g. conductive metals or organic materialswith high heat transference. Changes in the temperature sensor 206 areautomatically communicated to the CCM 204, which automatically relaysthe data stream to a remote DCU unit located either on the person, or toa collection station nearby.

An example of the utility of a temperature sensor incorporated into acontinuously monitoring HG system is seen for monitoring of an ovulationevent. Detectable physiological changes, such as temperature, occur whenthe egg is released from the ovary into the fimbrae of the fallopiantubes and eventually into the uterus. Fertilization of the ovulated eggmust occur within a narrow window (24 hours) of the ovulation event,making timing of sexual intercourse essential for a successfulfertilization event. Although detectable, the temperature changes areminute relative to basal body temperature. Therefore, establishment ofan accurate baseline temperature is critical for successful predictionof ovulation. Since basal body temperature is circadian in nature, thisrequires repeated temperature monitoring throughout the day in order toget accurate baseline values. The HG will continuously collect data andestablish accurate baseline values for a given time period. A rise intemperature as compared to the baseline values indicates onset ofovulation. Upon that detected rise, the data collection unit will alertthe patient through various communication systems, including. but notlimited to a remote paging system, telecommunications pathway, e-mail orother internet linkage, voice-mail linkage, through the patient's careprovider or other types of communications pathways.

In order to obtain repeatable core temperature readings, it is importantto select an appropriate site for placing the sensor system. One suchlocation would be an intrauterine or vaginal placement of the device. Inthis situation, the BIH/CCM assembly may be packaged in the form abiocompatible capsule or other non-irritating shape and would adhere tothe surface either through mechanical, e.g. adhesives, micro filamentsor hooks, or be held by physical placement, e.g. as a part of a largerloop or inserted device. In such a form, the BIH may mount additionalsensors beyond those of temperature, including sensors to detect cyclichormones, e.g. luteinizing hormone, follicle stimulating hormone,progesterone, estrogen, or their metabolites, or other biomoleculespassed into the reproductive tract that would serve as indicators offollicular status.

In general, monitoring temperature changes is important for otherphysiological conditions, including the early indication of short terminfectious states (general increase in temperature) a sign of shock(general decrease in temperature), non-compliance with therapeuticregime causing localized temperature shift (diabetes, hypertension), orlong term deviations or shifts in temperature which are indicators ofillness (arterial sclerosis) that are not easily detected with currentdiagnostic methods. In addition, monitoring temperature is routine instudies or situations where monitoring of patient vital signs isnecessary, such as in premature infants, infants, daycare children,geriatric patients or hospital situations.

Veterinary Applications of the HG for Monitoring Temperature Changes

Monitoring temperature changes is not only important for humans, butalso in the veterinary field. An increased temperature is a generalindicator of infection, and may be an important early indicator to stopthe spread of an infectious disease. One such agent responsible fordecreased production of milk in dairy cattle is Pasturella hemolytica.The information from a device that can detect changes in temperature canbe relayed to a data collection unit. The data is analyzed, allowing afanner to identify the individual through a unique ID assigned to theBIH/CCM device attached to the animal, and isolate the contagious animalbefore it spreads through the herd. Depending on the size of the animal,the device need not be miniaturized, circumventing the need forextensive engineering. The device could also monitor otherbioparameters, e.g. including those relating to general health,reproductive status, nutritional status or activity.

Other veterinary applications include the use of the device inmonitoring laboratory animals during experimental manipulations in orderto simplify the measurement of important physiological parameters, whichindicate the efficacy or non-efficacy of pharmaceutical or other typesof treatments. For example, laboratory rats may be equipped with aBIH/CCM assembly and monitored in a continuous or periodic fashion forvital signs, such as temperature, respiration, heart rate and otherphysiological parameters. BIH/CCM assemblies from several laboratoryrats may be transmitted to one DCU. The amount of BIH/CCM assembliestransmitting to one DCU may be limitless because of the encryption anddata identification transmission, as well as handshaking, protocolswhich will be employed. The DCU may then transmit data from theplurality of BIH/CCM assemblies to a remote database management systemfor further analysis and summarization of the data. This may potentiallystreamline the data gathering process, allowing more experiments to beconducted in a shorter period of time with no animal handling necessary.

Use of the HG to Monitor Physiological Parameters at the Surface of theSkin

Additional physiological parameters could be measured using the abovetechnology at the surface by replacing the temperature sensor devicewith another application appropriate sensor. Examples of this includeheart rate (pressure detector, strain gage, optical surface tension,electrical output or other technologies), respiration (pressuredetector, optical surface tension, strain gage, electrical output orother technology), electrocardiogram measurement (Ag/AgCl electrodes;other technologies), surface pH (some type of electrode), oxygenconsumption (Clark electrode, partial pressure of O₂, luminescentquenching) and other physiological parameters. Other surface monitorsinclude sensing chemical and biological elements such as non-invasiveglucose monitoring through the skin for diabetic patients.

Use of the HG for Vital Sign Monitoring in Patients

In addition to monitoring a single physiological parameter, multiplesensors could be incorporated onto the same BIH to allow multipleparameters to be measured simultaneously. These multiple parameters maybe measured by using one or more BIH assemblies that would contain oneor more sensors, appropriate to the application, e.g. pressure sensor todetermine HR and micro-cantilever to sense potassium discharge throughthe skin, measuring and communicating the collected values to the CCM,which would filter and combine the data and transmit to the DCU. The DCUwould then complete the signal processing and interpret (calculate) thesignals into the appropriate application specific format e.g. HeartRate, or use this data to then project or estimate a health parameterthat is highly correlated to the measured value, e.g. daily calorieconsumption. This would enable the continuous monitoring of the measuredsubjects vital signs, e.g. heart rate, respiration rate, potassiumdischarge in both a hospital setting, as well as in ambulatory use. Anexample of a use of the HG in vital sign monitoring is found for infantsthat may be predisposed to Sudden Infant Death Syndrome (SIDS) prematureinfants could be fitted with one or more BIH/CCM assemblies which wouldinclude sensors that monitor blood pressure, respiration, oxygenconsumption, heart rate, ECG and temperature. The unit is miniaturizedto decrease risk of removal or rejection by patient, as well as todecrease the surface area variability that may pose a problem forsmaller patients. In addition, the unit is thermally insulated todecrease the effects of volatile ambient environmental temperatures,such as those found in an incubator, may have on patient temperature.The sensors on the BIH can either be in direct communication with theCCM, or can communicate with the CCM wirelessly, such as through radiofrequency or other means of telemetry. Wireless connection of the CCMwith the BIH may prove advantageous for sensors that require multiplelocations to accurately determine physiological value. The CCM transmitsthe data stream generated by the multiple sensors on the BIH to the DCU.The DCU can collect sufficient data points to generate reliable currentvalues, and also monitor the patients condition such that upontriggering a pre-determined value, the uploading of information by theDCU into the remote data analysis system enables the clinician to bealerted if a measured parameter moves outside a preset range. Thisclinician alert can be provided through existing telecommunicationsystems or with the wireless data communication system with in the HG.

An alternative use of the multiple sensors system would be to monitormultiple parameters that when combined are statistically correlated toeither an illness or health maintenance factor. One such embodiment isthe use of temperature, heart rate, respiration rate and potassiumdischarge through the dermis in order to obtain an assessment ofkilo-calorie expenditure. This is envisioned as a method to bettermanage overall health with a measurement of energy expenditure to thatdiet and weight may be more precisely coordinated. Temperature sensorsinclude thermistors, metallic wire (such as platinum) resistivetemperature sensors, thermocouples, semi-conductor p/n junctions as wellas other silicon-based diode temperature sensors and band-gap basedsensors. Respiration rate may be monitored by chest cavity distensionand employ sensors such as strain gauges, including those based onWheatstone Bridge resistance change measurements, pressure transducersor bands worn around the chest coupled with strain gauges to evaluatechest expansion. Suitable ion specific microelectrodes or related sensordevices may measure potassium discharge. When combined, a profile ofthese measurements indicate energy consumption and coupled with otherpatient specific parameters such as weight, would describe kilo-calorieconsumption.

Use of the Hg for Non-Invasive Blood Pressure Monitoring in Patients

In addition to monitoring a multiple parameters on a single BIH, varioustypes of physiological parameters may be determined indirectly(correlated) or calculated from values obtained from a plurality ofnon-invasive or invasive BIH/CCM assemblies located on the measuredsubject, and using preset variables such as distance, time or locationin the calculation/correlation of the parameter.

An example of a multiple non-invasive BIH/CCM application would be thecalculation of blood pressure. The blood pressure would be calculated bythe DCU using measurement data acquired from two or more BIH/CCMassemblies with one or more of the sensors previously noted to measurethe physiological parameter (i.e. heart rate can be measured with apressure transducer sensor). This non-invasive system is of particularvalue to clinicians and patients today because of a prevalent conditioncalled the “White Coat” effect. This condition is experienced by manypatients today due to anxiety associated with being at their clinician'sfacility, causing their heart rate and blood pressure to be elevatedwhile in the clinician's facility. As a result, many patients are eithermisdiagnosed with hypertension or required to return to the careproviders facility numerous times to validate the clinicians diagnosis.By enabling clinicians to remotely, automatically and continuouslymonitor the patients blood pressure they would be enabled to betterdiagnosis the presence of hypertension and accordingly take thenecessary diagnostic actions.

Blood pressure can be calculated in the DCU by locating two BIH/CCMassemblies on the measured subject at a set distance or location. Bylocating at least two devices on the measure subject, separated at aspecified distance, then measuring the heart rate (diastole) from bothBIH/CCM devices, then transmitting this data and a time reference foreach of the measured values to the DCU. Then inputting into the DCUother relevant variables of the measured subject the Blood Pressurecould be calculated. Those inputted values could include the measuredsubjects gender, weight, height, age, and ethnicity.

In addition to providing the blood pressure values this applicationwould also enable clinicians and patients to monitor patients complianceto therapies prescribed or recommended by the clinician. By enablingeither direct measurement or calculation of parameters in a remotecontinuous environment changes in behavior and/or compliance can bedetected. Hypertension is typically treated with a therapeuticmedication that must be taken by the patient at clinician prescribedintervals e.g. every 8 hours, if the patient does not take themedication the illness may reappear i.e. blood pressure rises. Thisapplication of the technology would enable the detection ofnon-compliance and reminder to take their medication. The feature of theHG as a compliance monitor is applicable to most of the applicationsenvisaged including both the non-invasive and invasive applications.

Use of the HG to Monitor Blood Parameters in Patients

A HG may be configured to measure various physiological parameters ofblood. An invasive BIH assembly is implanted into the patient consistingof sensors that monitor oxygen levels, carbon dioxide, pressure, pH andother physiological parameters important in assessing patient health andcondition. The BIH assembly may itself consist of a needle, designed toself-insert into a vascularized compartment, such as a blood vessel. TheBIH assembly may also be inserted into the patient with the aid of asurgical instrument that makes a small incision and guides the BIHassembly into the patient, such as a trocar or other surgicalinstrument. In addition, surgical implantation techniques will be usedfor implants that are deeply embedded (i.e. below thehypodermis/subcutaneous layer) into the patient host. It is essentialthat all implantable devices be sterilized prior to insertion into thepatient.

The BIH assembly may comprise a flushing system, designed to decreasetrauma and adherence of the BIH assembly onto surrounding tissue. Thisbiofluidics system would contain physiological solutions, such assaline, and may also contain antibiotics, antifungal, antimicrobials, orother compounds designed to inhibit the growth of infection-causing organisms. The biofluidics system may also contain anti-inflammatoryagents as well as other agents to locally suppress the immune systemsurrounding the BIH assembly to decrease rejection incidence andincrease the longevity of the sensor unit.

After insertion of the BIH assembly, the assembly is adhered onto theskin with specialized adhesive biocompatible materials (transdermalpatch) that allow ventilation of the transdermal conduit whilemaintaining sterility of the assembly. The transdermal patch may becomprised of microporous nylon, thermoplastic microfibers,polypropylene, other polymers or other microporous films which form abarrier against extrinsic liquids, yet enable water vapors, i.e.perspiration and other bodily fluids, to flow freely through the fabric.The fabric should also insulate external conditions from influencing thefunction of the sensors, such as temperature, pressure, partial O₂pressure and other physiological parameters affected by extremeenvironmental conditions. The BIH assembly may communicate directly withthe CCM assembly through nylon tape, filaments or metal wireconnections, or communicate wirelessly via RF or any other telemetrytechnology, continuously transmitting data from the BIH sensors to theDCU. In order to decrease the risk of occlusion of the sensors oraccretion of biological materials onto the sensors that would hamperperformance, the biofluidics system may automatically flush thebiosampling access point area upon detection of build-up or adherence ofmaterial onto the sensor head or at defined time intervals.Alternatively, the region may be flushed either manually or uponreplacement of the biosensor component. The detection of biologicalmaterial build-up may be through sensors which sense changes in pressureor optical clarity of the environment immediately surrounding thesensors or by any other means that can detect accretion of biologicalmaterials that would hamper sensing ability. The transdermal conduitincision area may also be manually flushed periodically to decreaseadherence of biological materials on the sensor itself.

Data collection and analysis of signal output from the implanted BIHsensors will depend upon the implantation depth of the sensors.Subcutaneous implants could either transmit data to the CCM directlythrough nylon tape, filaments or insulated metal wire connections, orcommunicate wirelessly via RF or any other telemetry technology.Implants that are below the subcutaneous layer and into underlyingorgans may require wireless telemetry for communication of sensor datato either the CCM or DCU. This wireless transmission may be electrical(RF) or acoustic.

Use of the HG to Measure Glucose, Fructosime and Hemoglobin 1ac Levelsin Patients

The HG may be configured for measuring glucose, fructosime andHemoglobin 1ac levels in diabetic patients. Determining accurate levelsof these three elements is crucial to achieve metabolic control ofdiabetic patients in order to avoid hypo or hyperglycemic situations.Specific knowledge of glucose levels allows diabetics to self-regulateexercise, diet and insulin regimens, a condition crucial to avoidingadverse clinical situations. Traditional methods of monitoring glucoselevels includes multiple blood sampling, through finger pricking orother means, and measurement of glucose levels through glucoseoxidase/peroxidase calorimetric reaction.

Non-invasive methods of measuring glucose levels have been developed,including the use of reverse iontophoresis to measure glucose levels,the extraction of glucose from interstitial fluid and the use ofinfrared laser for measuring levels of glucose in fluids. Glucose sensormethods could be incorporated into the BIH assembly of the HG forcontinuous glucose monitoring. By doing this, more accurate baselinemeasurements could be obtained with automatic downloading of informationfrom the different sensor systems. Pre-set sensor levels could alert thepatient to hypo- or hyperglycemic levels through varioustelecommunication pathways, including a remote paging system,telecommunications pathway, e-mail or other internet linkage, voice-maillinkage, through the patient's care provider or other type ofcommunications pathway.

More elaborate sensors could also be used which may provide moreaccurate measurements than currently achieved with non-invasive glucosemonitoring systems. An implantable sensor with glucose oxidase at thetip of the BIH sensor would detect glucose through a calorimetricreaction, similar to what is obtained with current hand-held glucosemonitors. In addition, other sensor systems, such as electricaldetection, potentiometric detection, or any type of detection methodcould be used in conjunction with the BIH glucose sensing head. Forexample, deposition of glucose oxidase on self-assembled polypyrrolefilms would allow measurement of glucose levels through anelectron-transfer reaction, allowing levels to be determined accordingto the relative conductivity of the film (Ram et al, 1999).Self-calibrating structures (microchannels, vesicles, microcompartments)could be incorporated into the silicon wafer microstructures, allowingautomatic calibration of the sensor at set intervals throughout the day.

Use of the HG to Measure Drugs or Small Biomolecules

Drugs and other small biomolecules could be monitored using the abovetechnology at the surface by replacing the invasive glucose sensor onthe BIH with another appropriate sensor, depending upon the application.(This sensing may be also enabled with an application orally.) Drugmonitoring is useful for comparing the efficacy of drug treatmentregimens with levels of the compound in vivo in patients. Drugmonitoring also overcomes potential polymorphic differences betweenindividuals that could result in over- or underdosing of patients due todifferences in drug metabolizing enzyme activities. Drug sensors usedwould include specific antibody-loaded sensors, enzymes specific in themetabolism of various drug compounds (cytochrome P-450 enzymes, etc.)and other technologies utilized in the detection and measurement oftherapeutic pharmaceutical compounds. Sensors could also monitor drugtracers that pharmaceutical manufacturers routinely include intherapeutic formulations. Using tracers to monitor the presence of theprescription drug in the body may assist in determining compliance oreffectiveness of therapies, as well as identifying possible counterfeitformulations that may be in use by the patient.

Sensors that monitor the presence of illicit drugs could also beincorporated into a BIH. Sensors important for this application includethe monitoring of cocaine, heroin, marijuana, amphetamines and otherillicit compounds that would require monitoring on a regular basis. Anydetection of illicit compounds in an individual would result in theautomatic notification of the appropriate legal authorities. Inaddition, alcohol levels could be monitored by using pre-set levelsdetermined by the laws of each state. Upon the elevation of alcohollevels beyond these pre-set levels, an alarm would be triggered wherebythe appropriate authorities would be automatically notified. For boththe detection of illicit compounds and illegal alcohol levels, afeedback loop would also automatically disengage motor vehicleoperation, preventing the individual from operating any motor vehicleconnected to any of the telecommunication systems listed above.

Use of the HG in Monitoring Serum Proteins and Microorganisms

The HG could also be configured to measure serum protein levels. Forexample, levels of atherogenic markers, such as high-densitylipoprotein, low-density lipoprotein or lipoprotein-a may be measuredwith antibodies attached to the sensor head. The antibodies may beattached to microcantilever structures and detected through optical orpotentiometric methods, as described in U.S. Pat. Nos. 5,445,008 and6,016,686, incorporated herein by reference. Binding of the specificserum proteins to the antibodies may also be detected via colorimetricor electrochemical-mediated reactions. Other methods that are otherwiseknown to those of skill in the art are intended to be incorporated hereby reference, and may be used in conjunction with the methods describedhere.

In addition to the measurement of serum lipoproteins in blood,microorganisms, such a s Salmonella, E. coli, Streptococci, Chlamydiasp. (including C. trachomatis and C. pneumoniae), Pseudomonas, the HIVvirus and other microorganisms, may be detected through antibody,enzyme-mediated detection sensors or any other microorganism detectiontechnology. Of high importance is the monitoring of nosocomialinfections in hospital situations. A BIH sensor head may be configuredto contain not only vital sign measurement, but also detection ofinfectious organisms in patient samples. The sensor could be placed inan implantable platform, as above, but also in needles, catheters,respiratory implants or any other implants used in a hospital setting.The sensor could be queried using telemetry technology to continuouslymonitor the presence of infectious organisms, or directly linked to theBIH through electrical conduction means. The BIH could also be placed indevices or equipment adjacent to the patient for detection of the typesof materials being inserted/injected into the patient e.g. IntravenousPumps and Mechanisms, Respiratory devices, kidney dialysis systems,blood sampling systems and devices, fluid discharge containment devicese.g. bed pans, urine samples, sputum samples, oral sampling devices andsystems e.g. cotton swabs, tongue depressors, nasal secretion collectiondevices e.g. bulbs etc.

The BIH sensor, through a uterine or vaginal implantation device, couldalso measure the occurrence of uterine or vaginal infections, such asyeast (fungal) infections, Human Papilloma virus, Epstein Barr virus,sexually transmitted agents, or other uterine or vaginal infection. Forexample, yeast infections could be monitored through the specificdetection of agents, such as Candida albicans, by antibody-mediateddetection, enzyme detection, or other means routinely used in detectingCandida infections. In addition, a second sensor monitoring pH levelsmay also be incorporated. pH levels are indicative of ideal environmentsfor Candida growth, where a decrease in the acidity of the vaginalenvironment releases growth inhibition of Candida, and transforms themicrobe from a yeast-like to an invasive fuigal mycellium form. Earlydetection of changes in physiological parameters or presence ofmicrobial agents is essential in the prevention and treatment of diseasestates, including Chronic Fatigue Syndrome.

Use of the HG for Oral Measurements

The mouth is a less commonly employed site of bioparameter measurementsbut offers a number of significant advantages, including the ability toaccess body fluids and to monitor exhaled gases. In certain instances,these may serve as alternative measurements to invasive techniques.Using suitable sensors, e.g. a microcantilever MEMS systems, it ispossible to measure ketone or aldehyde content within saliva andtherefore gauge dietary/nutritional status (e.g. catabolic dietarydeficiency) or, for the purpose of breath acceptability in socialsettings. In other applications, exposure to chemical or biologicalwarfare agents may be assessed by placing within the buccal cavitysuitable sensor systems e.g. those for volumetric measurements of oxygenconsumption (or partial pressure of oxygen gas, or other gases such ascyanide, Lewisite, or specific toxins or agents. In addition, an oraldevice could be used to ensure compliance to a therapeutic regimen byanalyzing the exhaled gases or fluids within the mouth for markers orother chemical or biological elements that would correlate to theconcentration of the therapeutic in the measured subject.

In use, a BIH/CCM system may be affixed to the outside surface of theteeth. Alternatively, a combined BIH/CCM may be placed or positionedbetween teeth and held in place by dental floss or other similar typedevice.

Use of the HG for Measurement of Other Biological Parameters

Measurement of other biological parameters that were not contemplated inthe preceding examples may be accomplished using the above system byincorporating the appropriate sensor into the HG. For instance, it maybe readily envisaged how one skilled in the art might utilize a HGsystem to augment hearing in select circumstances by placing an acousticsensor/transmitter BIH assembly within the ear as a cochlear implant andutilize the CCM to transmit data representing audible sounds to the ear.In addition, it will be understood that the present invention may beimplemented using other technologies, including direct digital readoutof signal output from the sensor platform, and other technologies knownto those of skill in the art. All such variations and modifications areintended to be within the scope of the invention claimed by this patent.

1. A system for ambulatory physiological monitoring comprising: at leastone adhesive patch positioned on at least a portion of a subject, saidpatch comprising a plurality of sensors and at least one communicationmodule, said sensors being configured to sense one or more physiologicalparameters comprising at least electrical impedance; a data collectionunit configured to receive information collected from said sensors fromsaid communication unit.
 2. The system of claim 1, additionallycomprising a remote data management system configured to receiveinformation from said data collection unit and process said information.3. The system of claim 1, wherein said adhesive patch is secured to atleast a portion of a thorax of said subject.
 4. The system of claim 1,additionally comprising a temperature sensor.
 5. The system of claim 1,additionally comprising a subsurface temperature sensor.
 6. The systemof claim 1, wherein said data collection unit is also configured toprocess information before sending information to said remote datamanagement system.
 7. The system of claim 1, comprising a timer forassociating at least one measurement with an absolute time themeasurement was taken.
 8. The system of claim 1, wherein said remotedatabase is configured to establish an individual baseline parametervalue.
 9. The system of claim 1, wherein the data management systemprovides feedback to the data collection unit and/or the communicationmodule.
 10. The system of claim 1, wherein said feedback comprisesdiagnostic knowledge.
 11. The system of claim 1, wherein said feedbackcomprises actions and/or instructions.
 12. The system of claim 1,comprising a plurality of communication modules.
 13. The system of claim1, comprising a plurality of data collection units.
 14. A devicecomprising: a portable hydration monitoring probe dimensioned to becontinuously borne by an organism, the probe comprising a supply ofelectrical power, at least one electrode to exchange electrical energyfrom the supply with a local portion of the organism bearing the probe,a controller to generate data representing a result of the hydrationmonitoring, the result reflecting a local bioelectric impedance based onthe exchange of electrical energy at the electrode, and a datacommunication device configured to wirelessly communicate the datarepresenting the hydration monitoring result to a remote apparatus. 15.The device of claim 14, wherein said portable hydration monitoring probeis configured as a patch probe.
 16. The device of claim 14, additionallycomprising a temperature sensor.
 17. The device of claim 14, comprisinga plurality of electrodes.
 18. The device of claim 17, wherein saidelectrodes are attached to an adhesive patch configured to be applied tothe skin of a subject.